scholarly journals Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5448
Author(s):  
Viola Hedrich ◽  
Kristina Breitenecker ◽  
Leila Djerlek ◽  
Gregor Ortmayr ◽  
Wolfgang Mikulits
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinases ◽  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Protein S ◽  
Immune Checkpoint Blockade ◽  
Tam Receptors ◽  
Novel Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, showing high mortality of patients due to limited therapeutic options at advanced stages of disease. The receptor tyrosine kinases Tyro3, Axl and MerTK—belonging to the TAM family—exert a large impact on various aspects of cancer biology. Binding of the ligands Gas6 or Protein S activates TAM receptors causing homophilic dimerization and heterophilic interactions with other receptors to modulate effector functions. In this context, TAM receptors are major regulators of anti-inflammatory responses and vessel integrity, including platelet aggregation as well as resistance to chemotherapy. In this review, we discuss the relevance of TAM receptors in the intrinsic control of HCC progression by modulating epithelial cell plasticity and by promoting metastatic traits of neoplastic hepatocytes. Depending on different etiologies of HCC, we further describe the overt role of TAM receptors in the extrinsic control of HCC progression by focusing on immune cell infiltration and fibrogenesis. Additionally, we assess TAM receptor functions in the chemoresistance against clinically used tyrosine kinase inhibitors and immune checkpoint blockade in HCC progression. We finally address the question of whether inhibition of TAM receptors can be envisaged for novel therapeutic strategies in HCC.

scholarly journals The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4443
Author(s):  
Ankit Patel ◽  
Masanori Oshi ◽  
Li Yan ◽  
Ryusei Matsuyama ◽  
Itaru Endo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Unfolded Protein Response ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Immune Cell ◽  
Histological Grade ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.

scholarly journals Prediction of Hepatocellular Carcinoma Prognosis and Immune Cell Infiltration Using Gene Signature Associated with Inflammatory Response

2022 ◽  
Vol 2022 ◽  
pp. 1-24
Author(s):  
Bin-Bin Da ◽  
Shuai Luo ◽  
Ming Huang ◽  
Fei Song ◽  
Rong Ding ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Cox Regression ◽  
Inflammatory Responses ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Differential Analysis

It has been demonstrated that the inflammatory response influences cancer development and can be used as a prognostic biomarker in various tumors. However, the relevance of genes associated with inflammatory responses in hepatocellular carcinoma (HCC) remains unknown. The Cancer Genome Atlas (TCGA) database was analyzed using weighted gene coexpression network analysis (WGCNA) and differential analysis to discover essential inflammatory response-related genes (IFRGs). Cox regression studies, both univariate and multivariate, were employed to develop a prognostic IFRGs signature. Additionally, Gene Set Enrichment Analysis (GSEA) was used to deduce the biological function of the IFRGs signature. Finally, we estimated immune cell infiltration using a single sample GSEA (ssGSEA) and x-cell. Our results revealed that, among the major HCC IFRGs, two (DNASE1L3 and KLKB1) were employed to create a predictive IFRG signature. The IFRG signature could correctly predict overall survival (O.S) as per Kaplan-Meier time-dependent roc curves analysis. It was also linked to pathological tumor stage and T stage and might be used as a prognostic predictor in HCC. GSEA analysis concluded that the IFRG signature might influence the immune response in HCC. Immunological cell infiltration and immune checkpoint molecule expression differed in the high-risk and low-risk groups. As a result of our findings, DNASILE may play a role in the tumor microenvironment. However, more research is necessary to confirm the role of DNASE1L3 and KLKB1.

scholarly journals Host Immune Defense upon Fungal Infections with Mucorales: Pathogen-Immune Cell Interactions as Drivers of Inflammatory Responses

2020 ◽  
Vol 6 (3) ◽  
pp. 173
Author(s):  
Dolly E. Montaño ◽  
Kerstin Voigt
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Fungal Infections ◽  
Immune Defense ◽  
Rapid Progression ◽  
Tissue Necrosis ◽  
Inflammatory Processes ◽  
Novel Therapeutic Strategies ◽  
Potential Use ◽  
Pro Inflammatory Cytokines

During the last few decades, mucormycosis has emerged as one of the most common fungal infections, following candidiasis and aspergillosis. The fungal order responsible for causing mucormycosis is the Mucorales. The main hallmarks of this infection include the invasion of blood vessels, infarction, thrombosis, and tissue necrosis, which are exhibited at the latest stages of the infection. Therefore, the diagnosis is often delayed, and the rapid progression of the infection severely endangers the life of people suffering from diabetes mellitus, hematological malignancies, or organ transplantation. Given the fact that mortality rates for mucormycosis range from 40 to 80%, early diagnosis and novel therapeutic strategies are urgently needed to battle the infection. However, compared to other fungal infections, little is known about the host immune response against Mucorales and the influence of inflammatory processes on the resolution of the infection. Hence, in this review, we summarized our current understanding of the interplay among pro-inflammatory cytokines, chemokines, and the host-immune cells in response to mucoralean fungi, as well as their potential use for immunotherapies.

Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma

2020 ◽  
Vol 19 (17) ◽  
pp. 2120-2129 ◽  
Author(s):  
Sakineh Dadashpour ◽  
Tuba T. Küçükkılınç ◽  
Ayse Ercan ◽  
Seyed J. Hosseinimehr ◽  
Nima Naderi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Biological Evaluation ◽  
Kinase Assay ◽  
Drug Candidate ◽  
Surface Receptors ◽  
Anticancer Mechanism

Background: Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer. Objective: The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents. Methods: A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells. Results: Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition. Conclusion: Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.

scholarly journals Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2186
Author(s):  
Anna Tutusaus ◽  
Montserrat Marí ◽  
José T. Ortiz-Pérez ◽  
Gerry A. F. Nicolaes ◽  
Albert Morales ◽  
...  
Keyword(s):  
Vitamin K ◽  
Tyrosine Kinases ◽  
Vascular Function ◽  
Inflammatory Diseases ◽  
Protein S ◽  
Specific Gene ◽  
Biological Functions ◽  
Tam Receptors ◽  
Viral Mimicry

The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily of receptor tyrosine kinases (RTK), are key regulators of inflammation and vascular response to damage. TAM signaling, which has largely studied in the immune system and in cancer, has been involved in coagulation-related pathologies. Because of these established biological functions, the GAS6-PROS1/TAM system is postulated to play an important role in SARS-CoV-2 infection and progression complications. The participation of the TAM system in vascular function and pathology has been previously reported. However, in the context of COVID-19, the role of TAMs could provide new clues in virus-host interplay with important consequences in the way that we understand this pathology. From the viral mimicry used by SARS-CoV-2 to infect cells, to the immunothrombosis that is associated with respiratory failure in COVID-19 patients, TAM signaling seems to be involved at different stages of the disease. TAM targeting is becoming an interesting biomedical strategy, which is useful for COVID-19 treatment now, but also for other viral and inflammatory diseases in the future.

Expression of the vitamin K-dependent proteins GAS6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques

2011 ◽  
Vol 105 (05) ◽  
pp. 873-882 ◽  
Author(s):  
Begoña Hurtado ◽  
Xavier Muñoz ◽  
Pedro Recarte-Pelz ◽  
Nadia Garcia ◽  
Anna Luque ◽  
...  
Keyword(s):  
Vitamin K ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Carotid Arteries ◽  
Protein S ◽  
Tam Receptors ◽  
Atherosclerotic Plaque Formation ◽  
Mrna And Protein Expression ◽  
Advanced Stages ◽  
Human Carotid

SummaryThe GAS6/ProS-TAM system is composed of two vitamin K-dependent ligands (GAS6 and protein S) and their three protein tyrosine kinase receptors TYRO3, AXL and MERTK, known as the TAM receptors. The system plays a prominent role in conditions of injury, inflammation and repair. In murine models of atherosclerotic plaque formation, mutations in its components affect atherosclerosis severity. Here we used Taqman low-density arrays and immunoblotting to study mRNA and protein expression of GAS6, ProS and the TAM receptors in human carotid arteries with different degrees of atherosclerosis. The results show a clear down-regulation of the expression of AXL in atheroma plaques with respect to normal carotids that is matched by decreased abundance of AXL in protein extracts detected by immunoblotting. A similar decrease was observed in PROS1 mRNA expression in atherosclerotic carotids compared to the normal ones, but in this case protein S (ProS) was clearly increased in protein extracts of carotid arteries with increasing grade of atherosclerosis, suggesting that ProS is carried into the plaque. MERTK was also increased in atherosclerotic carotid arteries with respect to the normal ones, suggesting that the ProS-MERTK axis is functional in advanced human atherosclerotic plaques. MERTK was expressed in macrophages, frequently in association with ProS, while ProS was abundant also in the necrotic core. Our data suggest that the ProS-MERTK ligand-receptor pair was active in advanced stages of atherosclerosis, while AXL signalling is probably down-regulated.

Growth arrest-specific gene 6 (GAS6)

2008 ◽  
Vol 100 (10) ◽  
pp. 604-610 ◽  
Author(s):  
Laura Fernández-Fernández ◽  
Lola Bellido-Martín ◽  
Pablo García de Frutos
Keyword(s):  
Vitamin K ◽  
Tyrosine Kinases ◽  
Growth Arrest ◽  
Protein S ◽  
Membrane Receptors ◽  
Coagulation Cascade ◽  
Specific Gene ◽  
Plasma Vitamin ◽  
Tam Receptors ◽  
Mediators Of Inflammation

SummaryGAS6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. GAS6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition and having 40% sequence identity. Despite this, the low concentration of GAS6 in plasma and the pattern of tissue expression of GAS6 suggest a distinct function among vitamin-K dependent proteins. Indeed, GAS6 has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl and MerTK. GAS6 employs a unique mechanism of action, interacting through its vitamin K-dependent GLA (γ-carboxyglutamic acid) module with phosphatidylserine-containing membranes and through its carboxy-terminal LamG domains with the TAM membrane receptors. During the last years there has been a considerable expansion of our knowledge of the biology of TAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. The innate immune response and the coagulation cascade have been shown to be interconnected. Mediators of inflammation are essential in the initiation and propagation of the coagulation cascade, while natural anticoagulants have important anti-inflammatory functions. GAS6 represents a new player in this context, while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.

TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Blood ◽  
2014 ◽  
Vol 123 (16) ◽  
pp. 2460-2469 ◽  
Author(s):  
Jonathan H. M. van der Meer ◽  
Tom van der Poll ◽  
Cornelis van ‘t Veer
Keyword(s):  
Tyrosine Kinases ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Receptor Activation ◽  
Cell Type ◽  
Primary Hemostasis ◽  
Tam Receptors ◽  
And Migration ◽  
Receptor Family

Abstract TAM receptors (Tyro3, Axl, and Mer) belong to a family of receptor tyrosine kinases that have important effects on hemostasis and inflammation. Also, they affect cell proliferation, survival, adhesion, and migration. TAM receptors can be activated by the vitamin K–dependent proteins Gas6 and protein S. Protein S is more commonly known as an important cofactor for protein C as well as a direct inhibitor of multiple coagulation factors. To our knowledge, the functions of Gas6 are limited to TAM receptor activation. When activated, the TAM receptors have effects on primary hemostasis and coagulation and display an anti-inflammatory or a proinflammatory effect, depending on cell type. To comprehend the effects that the TAM receptors and their ligands have on hemostasis and inflammation, we compare studies that report the different phenotypes displayed by mice with deficiencies in the genes of this receptor family and its ligands (protein S+/−, Gas6−/−, TAM−/−, and variations of these). In this manner, we aim to display which features are attributable to the different ligands. Because of the effects TAM receptors have on hemostasis, inflammation, and cancer growth, their modulation could make interesting therapeutic targets in thromboembolic disease, atherosclerosis, sepsis, autoimmune disease, and cancer.

scholarly journals Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246050
Author(s):  
Matthew S. Coates ◽  
Eric W. F. W. Alton ◽  
Garth W. Rapeport ◽  
Jane C. Davies ◽  
Kazuhiro Ito
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Syk Kinase ◽  
Low Concentrations ◽  
Mitogen Activated Protein ◽  
Syk Inhibitor

Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.

Density of CD8+ and CD68+ lymphocyte cell infiltration is associated with clinic outcome in hepatocellular carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15612-e15612
Author(s):  
Haibei Xin ◽  
Huan Chen ◽  
Lihong Wu ◽  
Yanhui Chen ◽  
Hongli Luo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Size ◽  
Immune Cell ◽  
Cox Regression ◽  
Association Studies ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Prognostic Signature ◽  
Cox Regression Analysis ◽  
Increasing Risk

e15612 Background: The achievements of immune checkpoint blockade strengthen the concept that tumor outgrowth and development are comprehensively regulated by immune system. The aim of the study was to explorer whether distinct infiltrated immune cell features differentially affect clinical outcome in hepatocellular carcinoma (HCC). Methods: We obtained respectable stage II HCC specimens, along with adjacent para-tumor tissues from 221 patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital, (in Shanghai, China) from 2015 through April 2018. CD8+ and CD68+ tumor-infiltrating lymphocytes (TILs) in the cancer area (CA) and stroma area (SA), as well as PD-1/PD-L1 expression, were analyzed by multiple immunohistochemistry. Results: The density of CD8+ TILs were significantly associated with gender, tumor size, and cirrhosis; while the density of CD68+ TILs were associated with copies of HBV DNA and anti-viral treatment. Multivariate Cox regression analysis revealed that high densities of CD8+ TILs and low densities of CD68+/CD8+ ratios independently predicted better outcomes. Of note, a prognostic signature combining clinic features [portal vein tumor thrombus (PVTT) and tumor size (TS)] and CD8+ TILs densities discriminated HCC patients into four subtypes with increasing risk of mortality: PVTT-negative/TS-small/CD8-high (6.8% of cases), PVTT-negative/TS-small/CD8-low (45.7%), PVTT-negative/TS-large (34.4%) and PVTT-positive (13.1%). Further association studies suggested that the four subgroups correlated with gender, tumor envelope, microvascular invasion (MVI), and SA-PD1 expression. Similarly, a prognostic signature combining PVTT, TS and CD68+/CD8+ ratios discriminated HCC patients into four subtypes with increasing risk of recurrence. Conclusions: Combined immune features including CD8+ and CD68+ lymphocyte infiltration and clinic characteristics are useful prognostic biomarkers for HCC patients.

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